PROJECT SUMMARY Vanderbilt requests funds for the purchase of a Nanion SynchroPatch 384 automated ?planar patch clamp? electrophysiology system. Patch-clamp electrophysiology is considered the ?gold standard? for measuring the activity of ion channels. Electrophysiology excels at measuring key functional properties of ion channels that are difficult or impossible to measure by other techniques, such as activation, inactivation, and deactivation kinetics, unitary or macroscopic conductance, and voltage dependence. Being able to measure these properties is critical for understanding mechanisms involved in modulation of ion channels by pharmacological agents, cell signaling pathways, and by disease-related mutations. Until recently, patch-clamp electrophysiology was an exceedingly slow, technically challenging, one-cell-at-a time technique. The advent of so-called ?planar patch clamp? technology has revolutionized patch clamping by replacing the pipette-based electrode with a planar glass substrate that avoids the technically challenging and slow spatial positioning of the pipette relative to the cells. The planar substrate is adhered to the bottom of a multi-well plate and is designed to catch a single cell or multiple cells for recordings. In 2008 Vanderbilt obtained a first-generation automated device, the Nanion PatchLiner. While useful, the 8-channel PatchLiner lacks the throughput to significantly impact the bottlenecks faced by Vanderbilt investigators. In the intervening years, devices that take advantage of the planar approach married with a traditional 384-well assay plate format stand have dramatically increased the throughput of patch clamp largely eliminating electrophysiology as a rate-limiting step in the advancement of our understanding ion channels? function in normal and pathophysiological settings. Vanderbilt has a history of excellence in ion channel research. Over the past decade Vanderbilt ion channel investigators have developed research programs focused on the discovery and development of small molecule ion channel modulators and the identification and characterization of disease related ion channel mutations. Although Vanderbilt investigators have been successful using fluorescence-based approaches to discover small molecules that modulate the activity of ion channels, these fluorescent approaches have substantial limitations that can be overcome by the strengths of the SynchroPatch. The sizeable disconnect between the throughput of fluorescence-based HTS approaches and traditional, one-cell-at-a-time patch clamp presents a bottleneck that severely limits our ability rapidly develop the potent and selective small molecule ion channel modulators. Similarly, Vanderbilt investigators who study a wide-range of mutations which are associated with disease are limited by the sheer number of mutations and complex phenotypes found in the human population. Applying the benefits of the SynchroPatch to both of these problems will decrease timelines by tens of folds.